tbuckley/cabot-search huggingface dataset:
First‐in‐human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy
Authors: Antonio Nieto, Ángel Mazón, María Nieto, Ethel Ibáñez, Dah‐Tay Jang, Susana Calaforra, Pilar Alba, Carmen Pérez‐Francés, Ruth Llusar, Javier Montoro, Antonio de Mateo, Remedios Alamar, David El‐Qutob, Javier Fernández, Luis Moral, Teresa Toral, Mónica Antón, Carmen Andreu, Ángel Ferrer, Isabel‐María Flores, Neus Cerdá, Sandra del Pozo, Raquel Caballero, José Luis Subiza, Miguel Casanovas
Journal: Allergy (2022)

Abstract Background Polymerized allergens conjugated to non‐oxidized mannan (PM‐allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM‐allergoids are readily taken up by DCs and induce Treg cells. This first‐in‐human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM‐allergoid (PM‐HDM) administered subcutaneously (SC) or sublingually (SL). Methods In a randomized, double‐blind, double‐dummy, placebo‐controlled trial, 196 subjects received placebo or PM‐HDM at 500, 1000, 3000, or 5000 mannan‐conjugated therapeutic units (mTU)/mL in 9‐arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. Results No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL ( p = 0.004) and 5000 mTU SC ( p = 0.011). CSMS improvement over placebo reached 70% ( p &lt; 0.001) in active 3000 mTU SC and 40% ( p = 0.015) in 5000 mTU SL groups. Conclusions PM‐HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.
Pevonedistat in East Asian patients with acute myeloid leukemia or myelodysplastic syndromes: a phase 1/1b study to evaluate safety, pharmacokinetics and activity as a single agent and in combination with azacitidine
Authors: Hiroshi Handa, June-Won Cheong, Yasushi Onishi, Hiroatsu Iida, Yukio Kobayashi, Hyeoung-Joon Kim, Tzeon-Jye Chiou, Koji Izutsu, Olga Tsukurov, Xiaofei Zhou, Helene Faessel, Ying Yuan, Farhad Sedarati, Douglas V. Faller, Akiko Kimura, Shang-Ju Wu
Journal: Journal of Hematology & Oncology (2022)

Abstract Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10–44 mg/m 2 , with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m 2 for co-administration with azacitidine 75 mg/m 2 in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients. Trial registration : clinicaltrials.gov: NCT02782468 25 May 2016. https://clinicaltrials.gov/ct2/show/NCT02782468
HDAC6 modulates myofibril stiffness and diastolic function of the heart
Authors: Ying-Hsi Lin, Jennifer L. Major, Tim Liebner, Zaynab Hourani, Joshua G. Travers, Sara A. Wennersten, Korey R. Haefner, Maria A. Cavasin, Cortney E. Wilson, Mark Y. Jeong, Yu Han, Michael Gotthardt, Scott K. Ferguson, Amrut V. Ambardekar, Maggie P.Y. Lam, Chunaram Choudhary, Henk L. Granzier, Kathleen C. Woulfe, Timothy A. McKinsey
Journal: Journal of Clinical Investigation (2022)

Passive stiffness of the heart is determined largely by extracellular matrix and titin, which functions as a molecular spring within sarcomeres. Titin stiffening is associated with the development of diastolic dysfunction (DD), while augmented titin compliance appears to impair systolic performance in dilated cardiomyopathy. We found that myofibril stiffness was elevated in mice lacking histone deacetylase 6 (HDAC6). Cultured adult murine ventricular myocytes treated with a selective HDAC6 inhibitor also exhibited increased myofibril stiffness. Conversely, HDAC6 overexpression in cardiomyocytes led to decreased myofibril stiffness, as did ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6. Modulation of myofibril stiffness by HDAC6 was dependent on 282 amino acids encompassing a portion of the PEVK element of titin. HDAC6 colocalized with Z-disks, and proteomics analysis suggested that HDAC6 functions as a sarcomeric protein deacetylase. Finally, increased myofibril stiffness in HDAC6-deficient mice was associated with exacerbated DD in response to hypertension or aging. These findings define a role for a deacetylase in the control of myofibril function and myocardial passive stiffness, suggest that reversible acetylation alters titin compliance, and reveal the potential of targeting HDAC6 to manipulate the elastic properties of the heart to treat cardiac diseases.
Abstract B005: Uncovering polygenic signatures of Ewings Sarcoma drug sensitivity during the evolution of resistance
Authors: Kristi Lin-Rahardja, Jessica Scarborough, Masahiro Hitomi, Jacob Scott
Journal: Cancer Research (2022)

Abstract Evolution of chemotherapeutic resistance can cause treatment failure in patients with metastatic Ewings sarcoma (EWS). As resistance to the first-line therapy evolves, there is potential for the tumor to develop sensitivities to other chemotherapeutic agents besides the active treatment. This concept is known as collateral sensitivity, and it presents an opportunity for medical providers to plan more effective treatment regimens. However, it can be difficult to predict due to the stochastic nature of evolution. By analyzing gene expression patterns among independent populations of an EWS cell line that have repeatedly evolved collateral responses, we aim to extract a collection of gene signatures, or sets of genes, that will predict states of collateral sensitivity against various existing chemotherapies. To accomplish this, we will treat independently evolving replicates of an EWS cell line (A673) with the standard of care therapy (alternating combinations of vincristine, doxorubicin, cyclophosphamide, and etoposide and cyclophosphamide) to evolve resistance. Throughout this treatment regimen, we will regularly screen for collateral sensitivity against 128 chemotherapeutic agents and perform bulk RNA-sequencing. When collateral sensitivity against a drug is observed in multiple replicates, we will utilize the RNA-sequencing data to extract gene signatures using differential expression analysis. The signatures will then be validated using patient-derived xenografts collected in our lab as well as from collaborators. When completed, the sizable archive of sensitivity signatures we expect to assemble could greatly streamline the process of treatment planning for EWS patients, especially those with advanced disease. When a patient's response to primary therapy begins to decline, RNA- sequencing can be performed on a tumor biopsy, gene expression patterns can be compared with the validated signature library, and the most appropriate drug for the individual patient can be determined and used for subsequent treatment. This proposed method of treatment planning mitigates the need for excessive treatment regimens that are not guaranteed to be effective for every patient, thereby expanding the reach of precision medicine and potentially improving outcomes for EWS patients. Citation Format: Kristi Lin-Rahardja, Jessica Scarborough, Masahiro Hitomi, Jacob Scott. Uncovering polygenic signatures of Ewings Sarcoma drug sensitivity during the evolution of resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B005.
An all-in-one adjuvanted therapeutic cancer vaccine targeting dendritic cell cytosol induces long-lived tumor suppression through NLRC4 inflammasome activation
Authors: Sao Puth, Vivek Verma, Seol Hee Hong, Wenzhi Tan, Shee Eun Lee, Joon Haeng Rhee
Journal: Biomaterials (2022)

Therapeutic cancer vaccines (TCVs) should induce robust tumor-specific T cell responses. To achieve this, TCVs incorporate T cell epitopes and strong adjuvants. Here, we report an all-in-one adjuvanted cancer vaccine platform that targets the intracellular compartment of dentritic cells and subsequently induces effective cytotoxic T cell responses. We screened a novel peptide (DCpep6) that specifically binds and transmits into CD11c+ cells through a novel in vivo phage biopanning. We then engineered a protein-based TCV (DEF) consisting of DCpep6 (D), an optimized HPV E7 tumor antigen (E), and a built-in flagellin adjuvant (F) as a single molecule. DEF was stably expressed, and each component was functional. In vivo-administered DEF rapidly biodistributed in draining LNs and internalized into CD11c+ cells. DEF immunization elicited strong antitumor T cell responses and provided long-term survival of TC-1 tumor-implanted mice. The DEF-mediated antitumor effect was abolished in NLRC4-/- mice. Taken together, we propose a protein-based all-in-one TCV platform that intracellularly codelivers tumor antigen and inflammasome activator to DCs to induce long-lasting antitumor T cell responses.
TripletGO: Integrating Transcript Expression Profiles with Protein Homology Inferences for Gene Function Prediction
Authors: Yi-Heng Zhu, Chengxin Zhang, Yan Liu, Gilbert S. Omenn, Peter L. Freddolino, Dong-Jun Yu, Yang Zhang
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Gene Ontology (GO) has been widely used to annotate functions of genes and gene products. Here, we proposed a new method, TripletGO, to deduce GO terms of protein-coding and non-coding genes, through the integration of four complementary pipelines built on transcript expression profile, genetic sequence alignment, protein sequence alignment, and naïve probability. TripletGO was tested on a large set of 5754 genes from 8 species (human, mouse, Arabidopsis, rat, fly, budding yeast, fission yeast, and nematoda) and 2433 proteins with available expression data from the third Critical Assessment of Protein Function Annotation challenge (CAFA3). Experimental results show that TripletGO achieves function annotation accuracy significantly beyond the current state-of-the-art approaches. Detailed analyses show that the major advantage of TripletGO lies in the coupling of a new triplet network-based profiling method with the feature space mapping technique, which can accurately recognize function patterns from transcript expression profiles. Meanwhile, the combination of multiple complementary models, especially those from transcript expression and protein-level alignments, improves the coverage and accuracy of the final GO annotation results. The standalone package and an online server of TripletGO are freely available at https://zhanggroup.org/TripletGO/.
Incidence and Predictors of Atrial Fibrillation in Cardiac Sarcoidosis
Authors: Meri Niemelä, Valtteri Uusitalo, Pauli Pöyhönen, Jukka Schildt, Jukka Lehtonen, Markku Kupari
Journal: JACC. Cardiovascular imaging (2022)

In cardiac sarcoidosis (CS), the risk and predictors of new-onset atrial fibrillation (AF) are poorly known. The authors evaluated the incidence and characteristics of AF in newly diagnosed CS. The authors studied 118 patients (78 women, mean age 50 years) with AF-naive CS having undergone cardiac 18F-fluorodexoyglucose positron emission tomography (18F-FDG PET) at the time of diagnosis. Details of patient characteristics and medical or device therapy were collected from hospital charts. The PET scans were re-analyzed for presence of atrial and ventricular inflammation, and coincident cardiac magnetic resonance (CMR) studies and single-photon emission computed tomography (SPECT) perfusions were analyzed for cardiac structure and function, including the presence and extent of myocardial scarring. Detection of AF was based on interrogation of intracardiac devices and on ambulatory or 12-lead electrocardiograms. Altogether 34 patients (29%) suffered paroxysms of AF during follow-up (median, 3 years) with persistent AF developing in 7 patients and permanent AF in 4. The estimated 5-year incidence of AF was 55% (95% CI: 34%-72%) in the 39 patients with atrial 18F-FDG uptake at the time of diagnosis vs 18% (95% CI: 10%-28%) in the 79 patients without atrial uptake (P < 0.001). In cause-specific Cox regression analysis, atrial uptake was an independent predictor of AF (P < 0.001) with HR of 6.01 (95% CI: 2.64-13.66). Other independent predictors were an increased left atrial maximum volume (P < 0.01) and history of sleep apnea (P < 0.01). Ventricular involvement by PET, SPECT, or CMR was nonpredictive. Symptoms of AF prompted electrical cardioversion in 12 patients (35%). Three of the 34 patients (9%) experiencing AF suffered a stroke versus none of those remaining free of AF. In newly diagnosed CS, future AF is relatively common and associated with atrial inflammation and enlargement on multimodality cardiac imaging.
Functional genomic analysis delineates regulatory mechanisms of GWAS-identified bipolar disorder risk variants
Authors: Rui Chen, Zhihui Yang, Jiewei Liu, Xin Cai, Yongxia Huo, Zhijun Zhang, Ming Li, Hong Chang, Xiong-Jian Luo
Journal: Genome Medicine (2022)

Genome-wide association studies (GWASs) have identified multiple risk loci for bipolar disorder (BD). However, pinpointing functional (or causal) variants in the reported risk loci and elucidating their regulatory mechanisms remain challenging.We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) data from human brain tissues (or neuronal cell lines) and position weight matrix (PWM) data to identify functional single-nucleotide polymorphisms (SNPs). Then, we verified the regulatory effects of these transcription factor (TF) binding-disrupting SNPs (hereafter referred to as "functional SNPs") through a series of experiments, including reporter gene assays, allele-specific expression (ASE) analysis, TF knockdown, CRISPR/Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Finally, we overexpressed PACS1 (whose expression was most significantly associated with the identified functional SNPs rs10896081 and rs3862386) in mouse primary cortical neurons to investigate if PACS1 affects dendritic spine density.We identified 16 functional SNPs (in 9 risk loci); these functional SNPs disrupted the binding of 7 TFs, for example, CTCF and REST binding was frequently disrupted. We then identified the potential target genes whose expression in the human brain was regulated by these functional SNPs through eQTL analysis. Of note, we showed dysregulation of some target genes of the identified TF binding-disrupting SNPs in BD patients compared with controls, and overexpression of PACS1 reduced the density of dendritic spines, revealing the possible biological mechanisms of these functional SNPs in BD.Our study identifies functional SNPs in some reported risk loci and sheds light on the regulatory mechanisms of BD risk variants. Further functional characterization and mechanistic studies of these functional SNPs and candidate genes will help to elucidate BD pathogenesis and develop new therapeutic approaches and drugs.
Structure-oriented design strategy to construct NIR AIEgens to selectively combat gram (+) multidrug-resistant bacteria in vivo
Authors: Haidong Li, Mengyao Yang, Ji Seon Kim, Jeongsun Ha, Jingjing Han, Heejeong Kim, Yejin Cho, Jingyun Wang, Ki Taek Nam, Juyoung Yoon
Journal: Biomaterials (2022)
ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress
Authors: Xiaoding Wang, Guangyu Zhang, Subhajit Dasgupta, Erica L. Niewold, Chao Li, Qinfeng Li, Xiang Luo, Lin Tan, Anwarul Ferdous, Philip L. Lorenzi, Beverly A. Rothermel, Thomas G. Gillette, Christopher M. Adams, Philipp E. Scherer, Joseph A. Hill, Zhao V. Wang
Journal: Circulation Research (2022)

Background: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Methods: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. Results: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes‚ whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Conclusions: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
Selection Balancing at Innate Immune Genes: Adaptive Polymorphism Maintenance in Toll-Like Receptors
Authors: Piotr Minias, Michal Vinkler
Journal: Molecular Biology and Evolution (2022)

Abstract Balancing selection is a classic mechanism for maintaining variability in immune genes involved in host–pathogen interactions. However, it remains unclear how widespread the mechanism is across immune genes other than the major histocompatibility complex (MHC). Although occasional reports suggest that balancing selection (heterozygote advantage, negative frequency-dependent selection, and fluctuating selection) may act on other immune genes, the current understanding of the phenomenon in non-MHC immune genes is far from solid. In this review, we focus on Toll-like receptors (TLRs), innate immune genes directly involved in pathogen recognition and immune response activation, as there is a growing body of research testing the assumptions of balancing selection in these genes. After reviewing infection- and fitness-based evidence, along with evidence based on population allelic frequencies and heterozygosity levels, we conclude that balancing selection maintains variation in TLRs, though it tends to occur under specific conditions in certain evolutionary lineages rather than being universal and ubiquitous. Our review also identifies key gaps in current knowledge and proposes promising areas for future research. Improving our understanding of host–pathogen interactions and balancing selection in innate immune genes are increasingly important, particularly regarding threats from emerging zoonotic diseases.
Penetrance of Deleterious Clinical Variants
Authors: Lisa Bastarache, Josh F. Peterson
Journal: JAMA (2022)

To the Editor A recent study1 highlighted how electronic health record (EHR)–linked biobanks can be used to investigate penetrance in a diverse population and concluded that most pathogenic variants have low penetrance, using data from 2 large biobanks—BioMe and UK Biobank.
Correction: How to solve misplacement of a lumen-apposing metal stent during cholecystogastrostomy: immediately perform a second one!
Authors: Benedetto Mangiavillano, Francesco Auriemma, Danilo Paduano, Laura Lamonaca, Federica Spatola, Alessandro Repici
Journal: Endoscopy (2022)

Correction to: How to solve misplacement of a lumen-apposing metal stent during cholecystogastrostomy: immediately perform a second one!Endoscopy 2022; 54(08): E421-E422DOI: 10.1055/a-1583-8947
Disparities in Risk of Advanced-Stage Liver Cancer and Mortality by Race and Ethnicity
Authors: Delfino Y Li, Trang VoPham, Mei-Tzu C Tang, Christopher I Li
Journal: JNCI Journal of the National Cancer Institute (2022)

In the United States, liver cancer is the fifth and seventh most common cause of cancer-related death among men and women, respectively. Compared with other racial or ethnic groups in the United States, Asian and Pacific Islander populations experience the highest incidence rates of liver cancer, but little is known about disparities in risk of advanced-stage disease or risk of liver cancer mortality across these heterogenous populations.In a population-based cohort of 60 146 patients aged 20-79 years diagnosed with liver cancer from 2004 to 2018 identified through the Surveillance, Epidemiology, and End Results Program, we examined associations between race or ethnicity, including specific Asian and Pacific Islander subgroups, and risk of advanced-stage liver cancer and liver cancer-specific mortality.Compared with non-Hispanic White patients, non-Hispanic Black, Filipino, and Laotian patients had 30%-85% elevated odds of being diagnosed with stage IV liver cancer, whereas Hispanic, Vietnamese, and Chinese patients had 7%-33% lower odds of being diagnosed with stage IV liver cancer (all P <.05). Additionally, non-Hispanic Black, Kampuchean, and Laotian patients had 6%-22% elevated hazards of liver cancer-specific mortality, and Hispanic, Vietnamese, Chinese, and Korean patients had 3%-27% lower hazards of liver cancer-specific mortality (all P <.05). All statistical tests were 2-sided.Substantial variations in risk of advanced-stage liver cancer and risk of liver cancer mortality were observed by race and ethnicity, including considerable heterogeneity across individuals broadly defined as Asians and Pacific Islanders. Further efforts to understand the contributors to these disparities are needed to inform potential targeted screening and treatment interventions.